Most recent update(s): Pre-exposure prophylaxis: The National Institutes of Health (NIH) COVID-19 guidelines recommend against the use of any drugs for SARS-CoV-2 pre-exposure prophylaxis, except in the setting of a clinical trial. Postexposure prophylaxis: The NIH COVID-19 guidelines recommend against the use of hydroxychloroquine for SARS-CoV-2 postexposure prophylaxis. Treatment: An emergency use authorization for hydroxychloroquine in the treatment of COVID-19 was issued by the FDA in March 2020 and subsequently revoked in June 2020 due to safety concerns and lack of efficacy (FDA 2020). NIH and Infectious Diseases Society of America COVID-19 guidelines recommend against the use of hydroxychloroquine, with or without azithromycin, for the treatment of COVID-19.
As part of our response to the evolving COVID-19 pandemic, published literature and guidelines from major health organizations are continuously monitored for potential content updates. At this time, only investigational medications with data determined to be of relatively high quality and/or consistently showing positive clinical outcomes to support dosing recommendations will be included in the monograph, outside of this Special Alert field.
Further information may be found at:
ClinicalTrials.gov: https://clinicaltrials.gov/ct2/results?cond=Covid19&term=hydroxychloroquine&cntry=&state=&city=&dist=
IDSA: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
Note: Dosage forms: Variable daily dosing (eg, alternating or skipping doses on certain days each week) may be used to obtain the recommended dose for rheumatologic uses. All doses below are expressed as hydroxychloroquine sulfate salt. Hydroxychloroquine sulfate salt 200 mg is equivalent to hydroxychloroquine base 155 mg. Safety: To avoid retinopathy and permanent vision loss, do not exceed recommended maximum doses. Baseline and periodic screening for retinopathy is necessary for rheumatologic uses and in long-term therapy (eg, >1 to 5 years depending on patient risk factors) (AAO [Marmor 2016]; Travassos 2019). Tolerability: GI upset (nausea, vomiting, diarrhea) is a common adverse effect. Dividing doses, taking with food, and, if appropriate, gradual dose escalation (in treating rheumatologic diseases) may improve tolerability (Wallace 2020).
Dermatomyositis, cutaneous (off-label use): Note: Used in combination with antipruritic medications, topical therapy, and nonpharmacologic measures (eg, photoprotection) (Targoff 2022; Vleugels 2020).
Oral: 300 to 400 mg daily as a single daily dose or in 2 divided doses. Assess response after 3 months; may attempt to slowly taper after several months of satisfactory response (Ang 2005; James 1985; Targoff 2022; Vleugels 2020; Woo 1984). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (AAO [Marmor 2016]; Melles 2014; Petri 2020b; Wallace 2020; manufacturer's labeling).
Lupus erythematosus:
Systemic lupus erythematosus: Note: In general, hydroxychloroquine (or chloroquine) is indicated for all patients with systemic disease; additional therapy is individualized according to predominant disease manifestations and activity (Lam 2016; Tsang-A-Sjoe 2015; Wallace 2020).
Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (AAO [Marmor 2016]; Melles 2014; Petri 2020b; Wallace 2020; manufacturer's labeling).
Discoid lupus erythematosus and subacute cutaneous lupus erythematosus: For use if response to local therapy is inadequate or impractical due to widespread skin lesions (Clarke 2020; Kuhn 2017):
Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (AAO [Marmor 2016]; Melles 2014; Petri 2020b; Wallace 2020; manufacturer's labeling).
Malaria (alternative agent):
Prophylaxis: Note: Only for use in individuals traveling to malarious regions without chloroquine resistance (CDC Yellow Book 2020).
Oral: 400 mg once weekly on the same day each week; begin 1 to 2 weeks before travel to malarious area; continue therapy while in malarious area and for 4 weeks after leaving the area (CDC Yellow Book 2020).
Treatment, uncomplicated: Note: Only for treatment of nonsevere infections caused by chloroquine-sensitive malaria; for infection caused by Plasmodium vivax or Plasmodium ovale, give in combination with primaquine. Not recommended for treatment if chloroquine or hydroxychloroquine was given for chemoprophylaxis (CDC 2020; WHO 2015).
Oral: 800 mg once, followed by 400 mg at 6, 24, and 48 hours after initial dose (total dose: 2 g) (CDC 2020; WHO 2015).
Porphyria cutanea tarda (off-label use): Oral: 100 mg twice weekly; continue until plasma or urine porphyrin levels are normal for at least several months (Singal 2012; Singal 2021).
Primary Sjögren syndrome (off-label use): Note: For treatment of moderate to severe extraglandular manifestations (eg, arthralgias, myalgias, fatigue) or milder symptoms unresponsive to nonpharmacologic measures and nonsteroidal anti-inflammatory drugs (NSAIDs) (Carsons 2017; Demarchi 2017; Fox 1996; Kruize 1993; Mavragani 2006); some experts also use in patients with major salivary enlargement resulting in cosmetic concerns or glandular pain (Baer 2019).
Oral: Initial: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Gottenberg 2014; Kruize 1993; Mavragani 2006). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (AAO [Marmor 2016]; Melles 2014; Petri 2020b; Wallace 2020; manufacturer's labeling).
Q fever (Coxiella burnetii) (off-label use): Note: Given higher dose recommendations for Q fever, the CDC recommends routine therapeutic drug monitoring and ophthalmic exams for retinal toxicity (CDC [Anderson 2013]).
Persistent localized infection (eg, endocarditis, osteomyelitis, vascular infection, prosthetic joint infection) in nonpregnant patients: Oral: 600 mg/day in 1 or 3 divided doses in combination with doxycycline for ≥18 months, depending on site of infection and serologic response; in prosthetic valve disease or vascular infection, extend treatment to ≥24 months (CDC [Anderson 2013]; Raoult 2021).
Prevention of persistent infection following acute Q fever: Note: Generally reserved for patients with valvulopathy/cardiomyopathy or antiphospholipid antibodies (CDC [Anderson 2013]; Million 2013; Raoult 2021) or postpartum women with persistent serologic evidence of infection >12 months after delivery (CDC [Anderson 2013]).
Oral: 600 mg/day in 1 or 3 divided doses in combination with doxycycline for 12 months; patients with detectable antiphospholipid antibodies should receive treatment until levels normalize (CDC [Anderson 2013]; Million 2013; Raoult 2021).
Rheumatoid arthritis: Note: May be used as monotherapy (alternative agent) in patients with mild or limited disease without poor prognostic factors. May also be used in patients with moderate to severe disease regardless of prognostic factors in combination with other nonbiologic disease-modifying antirheumatic drugs (ACR [Singh 2016]; EULAR [Smolen 2014]; Kumar 2013; O’Dell 2013; Rath 2010; Smolen 2016).
Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Kumar 2013). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (AAO [Marmor 2016]; Melles 2014; Petri 2020b; Wallace 2020; manufacturer's labeling).
Sarcoidosis (off-label use):
Arthropathy: Note: As additional therapy for NSAID-resistant symptoms in patients with an inadequate response to glucocorticoids or who are unable to fully taper (ASG [Agarwal] 2018; Aggarwal 2021).
Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Therapy may be continued for ~1 year and then gradually tapered in patients who have responded and are stable on therapy (Aggarwal 2021). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (AAO [Marmor 2016]; Melles 2014; Petri 2020b; Wallace 2020; manufacturer's labeling).
Cutaneous disease, extensive: Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses for ≥3 months to evaluate for efficacy; if there is satisfactory improvement, may consider gradual tapering and discontinuation if response is maintained (Modi 2008; Prystowsky 2021). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (AAO [Marmor 2016]; Melles 2014; Petri 2020b; Wallace 2020; manufacturer's labeling).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Mild to severe impairment: There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Tett 1993); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (expert opinion).
Hemodialysis: Not dialyzable (Jallouli 2015): There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Tett 1993); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (expert opinion).
Peritoneal dialysis: There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Tett 1993); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (expert opinion).
CRRT: Unlikely to be dialyzable (Barlow 2020): There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Tett 1993); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (expert opinion).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
(For additional information see "Hydroxychloroquine: Pediatric drug information")
Note: All doses below expressed as hydroxychloroquine sulfate. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base. To avoid retinopathy and permanent vision loss, do not exceed recommended maximum doses. Baseline and periodic screening for retinopathy is necessary for rheumatologic uses and in long-term therapy (eg, >1 to 5 years depending on patient risk factors) (AAO [Marmor 2016]).
Malaria:
Chemoprophylaxis: Note: Only for use in individuals traveling to malarious regions without chloroquine resistance (CDC Yellow Book 2020).
Infants, Children, and Adolescents: Oral: 6.5 mg/kg hydroxychloroquine sulfate once weekly on the same day each week; maximum dose: 400 mg/dose hydroxychloroquine sulfate; begin 1 to 2 weeks before travel to malarious area; continue while in malarious area and for 4 weeks after leaving the area (CDC Yellow Book 2020).
Treatment, uncomplicated: Infants, Children, and Adolescents: Oral: Initial: 12.9 mg/kg/dose hydroxychloroquine sulfate (maximum initial dose: 800 mg/dose hydroxychloroquine sulfate); followed by 6.5 mg/kg hydroxychloroquine sulfate at 6, 24, and 48 hours after initial dose; maximum dose: 400 mg/dose hydroxychloroquine sulfate. For infection caused by Plasmodium vivax or Plasmodium ovale, use in combination with appropriate antirelapse treatment (ie, primaquine) (CDC 2020).
Juvenile dermatomyositis, skin predominant: Limited data available: Children and Adolescents: Oral: 5 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 400 mg/day. Dosage range reported: 2 to 6 mg/kg/day (CARRA [Kim 2017]; Kliegman 2020; Olson 1989); however, some experts recommend a maximum of 5 mg/kg/day to mitigate risk of retinal toxicity (AAO [Marmor 2016]). Use in combination with nonpharmacologic measures (eg, photoprotection), topical therapies, and/or other systemic therapies (CARRA [Kim 2017]; Kliegman 2020; Olson 1989).
Systemic lupus erythematosus (SLE): Limited data available: Children and Adolescents: 4 to 6.5 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 400 mg/day (EULAR [Fanouriakis 2019]; Marks 2010; Thorbinson 2016); based upon data in adults, some experts recommend a maximum of 5 mg/kg/day to mitigate risk of retinal toxicity (AAO [Marmor 2016]); Costedoat-Chalemeau 2019; EULAR [Fanouriakis 2019]; Fanouriakis 2020).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function: Infants, Children, and Adolescents:
Note: Renal clearance accounts for 15% to 25% of total clearance (Tett 1993).
Mild to severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.
Hemodialysis: Not dialyzable (Jallouli 2015): There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.
Peritoneal dialysis: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.
Continuous renal replacement therapy (CRRT): Unlikely to be dialyzable based on wide volume of distribution and high lipophilicity (Barlow 2020): There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Refer to adult dosing.
Rheumatic diseases (eg, rheumatoid arthritis, lupus erythematosus, primary Sjögren syndrome [off-label use]): Available data do not specifically address dosing in obese patients; however, some experts recommend standard daily doses (non-weight-based) up to a maximum of 400 mg/day in patients weighing ≥80 kg (Wallace 2020).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as sulfate:
Plaquenil: 200 mg [contains corn starch]
Generic: 100 mg, 200 mg, 300 mg, 400 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as sulfate:
Plaquenil: 200 mg
Generic: 200 mg
Oral: Administer with food or milk. Do not crush or divide film-coated tablets per the manufacturer; the tablets have a bitter taste (McLaughlin 1991). In patients unable to swallow tablets, it has been recommended that tablets may be crushed and mixed with a small amount of applesauce, chocolate syrup, or jelly (CDC Yellow Book 2020), or an extemporaneous suspension may be compounded (See Extemporaneously Prepared).
Oral: Administer with food or milk. Do not crush or divide film-coated tablets per the manufacturer; the tablets have a bitter taste (McLaughlin 1991). In patients unable to swallow tablets, it has been recommended that tablets may be crushed and mixed with a small amount of applesauce, chocolate syrup, or jelly (CDC Yellow Book 2020), or an extemporaneous suspension may be compounded (See Extemporaneous Preparations).
Lupus erythematosus: Treatment of chronic discoid erythematosus and systemic lupus erythematosus in adults.
Malaria: Treatment of uncomplicated malaria caused by susceptible strains of Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium falciparum; prophylaxis of malaria in geographic areas where chloroquine resistance is not reported. Note: The CDC guidelines also recommend hydroxychloroquine for chloroquine-sensitive Plasmodium knowlesi malaria (CDC 2020).
Limitations of use: Hydroxychloroquine is not effective against chloroquine- or hydroxychloroquine-resistant malaria strains of Plasmodium species; not recommended for treatment of complicated malaria, malaria prophylaxis in regions with chloroquine resistance, or treatment when the Plasmodium species has not been identified; hydroxychloroquine alone does not prevent relapses of P. vivax and P. ovale infections because it is not effective against the hypnozoite liver stage forms of these parasites.
Rheumatoid arthritis: Treatment of acute and chronic rheumatoid arthritis in adults.
Dermatomyositis, cutaneous disease; Porphyria cutanea tarda; Primary Sjögren syndrome (extraglandular manifestations); Q fever (Coxiella burnetii); Sarcoidosis, arthropathy; Sarcoidosis, cutaneous disease (extensive)
Hydroxychloroquine may be confused with hydrocortisone, hydroxyurea
Plaquenil may be confused with Platinol
A predominantly restrictive or diastolic cardiomyopathy presenting as heart failure has been reported following long-term use of antimalarials for rheumatic diseases (especially chloroquine but occasionally hydroxychloroquine); systolic impairment may also occur (Ref). Additionally, conduction abnormalities (eg, atrioventricular block, sick sinus syndrome, bundle branch block) and pulmonary hypertension have been reported (Ref). On imaging, myocardial hypertrophy is most common in patients who develop cardiomyopathy. Clinicians should note that some patients may not have any or very few clinical symptoms. Laboratory findings may include elevated creatine kinase, lactate dehydrogenase, and/or troponins (Ref). While some patients may experience improvement following discontinuation, others experience permanent damage that may result in the need for cardiac transplant or death (Ref).
Mechanism: Time-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to bind to phospholipids within the myocyte, leading to accumulation in lysosomes and inhibiting lysosomal enzymes in several tissues, including peripheral nerve, cardiac, and skeletal muscle. The resulting intracellular degradation leads to accumulation of metabolic products (eg, phospholipids, glycogen) (Ref).
Onset: Delayed (Ref); patients may remain clinically asymptomatic for a long period of time with symptoms only appearing at a later stage and/or with high cumulative doses (eg, several years of therapy) (Ref). Some patients may experience improvement within 1 month to 1 year following discontinuation, others experience permanent damage that may result in the need for cardiac transplant or death (Ref).
Risk factors:
The following confers an increased risk (Ref):
• Longer duration of therapy
• Higher cumulative doses
• Older age
• Females
• Preexisting cardiac disease
• Kidney impairment
Although the manufacturer's labeling recommends that hydroxychloroquine be used with caution in patients with glucose-6-phospate deficiency (G6PD) due to the potential for hemolysis (hemolytic anemia), there are limited data to support this risk. Many experts consider hydroxychloroquine, when given in usual therapeutic doses to WHO Class II and III G6PD deficient patients, to probably be safe (Ref). In a retrospective chart review, no incidence of hemolytic anemia was found among the 11 patients identified with G6PD deficiency receiving hydroxychloroquine therapy, despite >700 months of exposure (all patients were African-American and located in the US) (Ref). In addition, the ACR Rheumatology guidelines do not mention the need to evaluate G6PD levels prior to initiation of therapy (Ref).
Cutaneous hypersensitivity reactions ranging from maculopapular rash to severe cutaneous adverse reactions (SCARs) may occur. Various delayed, nonlife-threatening reactions have been reported, including lichenoid, urticarial, and maculopapular eruptions (Ref). Reported SCARs include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS [also known as drug hypersensitivity syndrome]), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (Ref). Hydroxychloroquine is also associated with phototoxic and photoallergic dermatitis (Ref).
Mechanism: Non-dose related; immunologic; delayed hypersensitivity reactions are mediated by T-cells or antibodies other than immunoglobulin E (IgE) (eg, IgG-mediated, such as some cytopenias) (Ref). SCARs are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref).
Onset: Varied; most nonlife-threatening cutaneous reactions occurred 5 to 14 days after initiation of hydroxychloroquine (Ref). Onset of SCARs is generally days to weeks after administration of the causative drug (Ref) but may occur more rapidly (usually within 1 to 4 days) upon reexposure (Ref).
Risk factors:
• Prior hypersensitivity reaction to 4-aminioquinolines. Note: There is conflicting evidence regarding cross-reactivity between the 4-aminoquinolines (eg, chloroquine, hydroxychloroquine), although most reports suggest tolerance of chloroquine in patients with nonsevere cutaneous reactions to hydroxychloroquine (Ref).
• Patients with dermatomyositis, in particular those with anti-small ubiquitin-like modifier 1 activating enzyme (anti-SAE-1/2) autoantibodies (Ref).
Severe hypoglycemia has rarely been reported in patients (both with and without diabetes) who were receiving hydroxychloroquine (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Chloroquine has been shown to reduce intracellular insulin degradation, increase intracellular insulin accumulation, slow receptor recycling, stimulate insulin-mediated glucose transport, and increase peripheral insulin sensitivity and secretion (Ref).
Onset: Unknown. In one case report, a patient was initiated on hydroxychloroquine and presented to the emergency department 2 months later with symptoms secondary to severe hypoglycemia (Ref).
Risk factors:
• Concomitant use of other medications known to lower blood glucose concentrations
Skeletal muscle myopathy or neuropathy leading to asthenia and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction have been reported (Ref). Symptoms ranged from painless proximal weakness in both upper and lower extremities to severe weakness requiring hospitalization and ventilatory support (Ref). Clinicians should note that patients with rheumatic disease may experience symptoms of their underlying disease that make diagnosis of myopathy difficult (Ref).
Mechanism: Time-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to bind to phospholipids within the myocyte, accumulating in lysosomes and inhibiting lysosomal enzymes in several tissues, including peripheral nerve, cardiac, and skeletal muscle. The resulting intracellular degradation leads to accumulation of metabolic products (eg, phospholipids, glycogen) (Ref). Muscle and nerve biopsies have been associated with curvilinear bodies and muscle fiber atrophy with vacuolar changes (Ref).
Onset: Delayed; varies from <1 year of therapy to >10 years (Ref). In addition, the response to discontinuation of hydroxychloroquine varies with some patients experiencing resolution of symptoms within weeks to months while others experience progression of symptoms (Ref).
Risk factors:
Risk factors are poorly defined but may include:
• White people (Ref)
• Kidney failure (Ref)
• Concomitant use of other myotoxic drugs, including corticosteroids (Ref)
Various neuropsychiatric effects have been described with antimalarial agents, including hydroxychloroquine. Symptoms have included hallucination, psychosis, psychomotor agitation, suicidal ideation, and suicidal tendencies (Ref).
Mechanism: Time-related; exact mechanism is not fully understood. Proposed hypotheses include a cholinergic imbalance related to the inhibition of the acetylcholinesterase, prostaglandin E antagonism, the accumulation of toxic metabolites in the lysosome, and the down-regulation of glycoprotein-P in the blood brain barrier (Ref).
Onset: Varied; reported onset varies greatly from weeks to years (Ref). One case report of psychiatric symptoms following use of chloroquine demonstrated that symptoms may persist for several months (Ref).
Risk factors:
• Family history of neuropsychiatric symptoms (Ref)
• Female patients (Ref)
• Concomitant administration of drugs known to increase hydroxychloroquine concentrations (Ref)
• Concomitant use of glucocorticoids (Ref)
• Concomitant use of alcohol (Ref)
• Low body weight (Ref)
Long-term use or high doses of antimalarials (especially chloroquine but also hydroxychloroquine) have been associated with prolonged QT interval on ECG and subsequent ventricular arrhythmias (including torsades de pointes [TdP]), syncope, and sudden cardiac death (Ref).
Mechanism: Dose-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to abnormally affect ion currents (including hyperpolarization activated ion channels, delayed rectifier potassium currents, and L-type calcium ion currents). This may cause delayed depolarization and prolonged repolarization of cardiac myocytes, which can lead to QT interval prolongation (Ref).
Onset: Varied; effect is concentration-dependent; therefore, timing may be impacted by high doses or accumulation. In one study in healthy subjects administered chloroquine (100 mg base per day; n=3), QT prolongation was noted on day 3 of administration (Ref)
Risk factors:
In general, risk factors for drug-induced QT prolongation include:
• Females (Ref)
• Structural heart disease (eg, history of myocardial infarction or heart failure) (Ref)
• Genetic defects of cardiac ion channels (Ref)
• Congenital long QT syndrome (Ref)
• Baseline QTc interval prolongation (eg, >450 msec) (Ref)
• Electrolyte disturbances (eg, hypokalemia or hypomagnesemia) (Ref)
• Bradycardia (Ref)
• Hepatic impairment (Ref)
• Kidney impairment (Ref)
• Coadministration of multiple medications that prolong the QT interval or drug interactions that increase serum concentration of QT-prolonging medications (Ref)
Long-term use of hydroxychloroquine may result in retinopathy characterized by parafoveal retinal damage (Ref). The clinical picture is classically characterized as a bilateral “bull's-eye” maculopathy; visual acuity generally remains intact until more severe damage has been realized. As retinopathy progresses, the area of functional deficit may expand to the foveal center with decreased visual acuity, peripheral vision, and night vision; cystoid macular edema may also occur. Clinicians should note that some patients may not experience symptoms during the early stages of retinopathy and that retinopathy is irreversible (Ref).
Mechanism: Time-related; exact mechanism is not fully understood. A proposed mechanism is impaired lysosomal degradation of photoreceptor outer segments by the retinal pigment epithelium (Ref).
Onset: Delayed; most commonly occurring >5 years after initiation of therapy (Ref).
Risk factors:
• High daily doses relative to body weight (>5 mg/kg actual body weight) and a duration of >5 years of use in the treatment of rheumatic diseases (Ref)
• Higher serum concentrations of hydroxychloroquine (Ref)
• Concurrent tamoxifen use (Ref)
• Kidney impairment (Ref)
• Lower body weight (Ref)
• Preexisting macular disease (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%: Ophthalmic: Retinopathy (4%; serum concentration dependent [Petri 2020b]; early changes reversible [may progress despite discontinuation if advanced])
<1%: Hematologic & oncologic: Hemolysis (rare; primarily a theoretical concern in patients with glucose-6-phosphate deficiency; data do not support withholding therapy in these patients [Luzzato 2016; Mohammad 2018])
Frequency not defined:
Cardiovascular: Sick sinus syndrome
Dermatologic: Alopecia (Sharma 2020), erythema multiforme, exacerbation of psoriasis, exfoliative dermatitis, hair discoloration, pruritus, skin photosensitivity (Sharma 2020), skin rash (Borik 2019), urticaria
Endocrine & metabolic: Exacerbation of porphyria, weight loss
Gastrointestinal: Abdominal pain, anorexia
Hematologic & oncologic: Agranulocytosis (rare) (Andrès 2017), anemia, aplastic anemia, bone marrow failure, leukopenia, thrombocytopenia
Hepatic: Abnormal hepatic function tests, acute hepatic failure
Hypersensitivity: Angioedema
Nervous system: Ataxia, dizziness, emotional lability, fatigue, headache, irritability, nervousness, nightmares, psychosis (Das 2014), seizure, sensorineural hearing loss, vertigo
Neuromuscular & skeletal: Asthenia, myopathy (including paralysis or neuromyopathy, leading to progressive weakness and atrophy of proximal muscle groups; may be associated with mild sensory changes and loss of deep tendon reflexes; Casado 2006)
Ophthalmic: Corneal changes (corneal edema, corneal opacity, corneal sensitivity, corneal deposits, visual disturbance, blurred vision, photophobia), decreased visual acuity, macular degeneration, maculopathy, nystagmus disorder, retinal pigment changes, retinitis pigmentosa, scotoma, vision color changes, visual field defect
Otic: Tinnitus
Respiratory: Bronchospasm
Postmarketing:
Cardiovascular: Atrioventricular block (Bae 2012), bundle branch block (Costedoat-Chalumeau 2007), cardiomyopathy (AHA [Page 2016]; Fiehn 2020; Tönnesmann 2012; Tönnesmann 2013), heart failure (Figliozzi 2021), prolonged QT interval on ECG (Chatre 2018; Chen 2006; O’Laughlin 2016; Stas 2008), torsades de pointes (Chatre 2018; O’Laughlin 2016), ventricular arrhythmia (Chatre 2018; O’Laughlin 2016), ventricular tachycardia (Abdelmaseih 2020)
Dermatologic: Acute generalized exanthematous pustulosis (Charfi 2015; Soria 2015), hyperpigmentation (Bahloul 2017; Sharma 2020), Stevens-Johnson syndrome (Leckie 2002), toxic epidermal necrolysis (Lateef 2009; Soria 2015)
Endocrine & metabolic: Hypoglycemia (Cansu 2008; FDA Safety Alert, April 1, 2020; Unübol 2011), severe hypoglycemia (Cansu 2008, Shojania 1999, Unübol 2011)
Gastrointestinal: Abdominal cramps (Abdelmaseih 2020), diarrhea (can be severe) (Abdelmaseih 2020), nausea (Abdelmaseih 2020), vomiting (Abdelmaseih 2020)
Hematologic & oncologic: Neutropenia (FDA Safety Alert, April 1, 2020), pancytopenia (FDA Safety Alert, April 1, 2020)
Immunologic: Drug reaction with eosinophilia and systemic symptoms (Soria 2015; Volpe 2008)
Nervous system: Confusion (FDA Safety Alert, April 1, 2020), delirium (FDA Safety Alert, April 1, 2020), extrapyramidal reaction (FDA Safety Alert, April 1, 2020), hallucination (Das 2014; FDA Safety Alert, April 1, 2020), psychomotor agitation (FDA Safety Alert, April 1, 2020; Manzo 2017), suicidal ideation (Mascolo 2018; Pinho de Oliveira Ribeiro 2013), suicidal tendencies (Mascolo 2018; Pinho de Oliveira Ribeiro 2013)
Ophthalmic: Epithelial keratopathy (Dosso 2007)
Renal: Renal insufficiency (FDA Safety Alert, April 1, 2020)
Respiratory: Pulmonary hypertension (Bae 2012)
Known hypersensitivity to hydroxychloroquine, 4-aminoquinoline derivatives, or any component of the formulation.
Canadian labeling: Additional contraindications (not in the US labeling): Preexisting retinopathy; use in children <6 years or weighing <35 kg
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction may be needed.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Jallouli 2012; MGFA 2020).
• Porphyria: Avoid use in patients with porphyria unless benefits outweigh risks; may exacerbate or precipitate disease.
• Psoriasis: Avoid use in patients with psoriasis unless benefits outweigh risks; may exacerbate or precipitate disease.
• Renal impairment: Use with caution in patients with renal impairment; dosage reduction may be needed.
Special populations:
• Glucose-6-phosphate dehydrogenase deficiency: Although the manufacturer's labeling recommends hydroxychloroquine be used with caution in patients with G6PD deficiency due to a potential for hemolytic anemia, there are limited data to support this risk. Many experts consider hydroxychloroquine, when given in usual therapeutic doses to the World Health Organization Class II and III G6PD deficient patients, to probably be safe (Cappellini 2008; Luzzatto 2016; Youngster 2010). In a retrospective chart review, no incidence of hemolytic anemia was found among the 11 patients identified with G6PD deficiency receiving hydroxychloroquine therapy, despite >700 months of exposure (all patients were African American and located in the United States) (Mohammad 2018). In addition, the American College of Rheumatology guidelines do not mention the need to evaluate G6PD levels prior to initiation of therapy (ACR [Singh 2016]).
• Pediatric: Pediatric patients have an increased sensitivity to aminoquinolines.
Substrate of CYP2D6 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Agalsidase Alfa: Hydroxychloroquine may diminish the therapeutic effect of Agalsidase Alfa. Risk C: Monitor therapy
Agalsidase Beta: Hydroxychloroquine may diminish the therapeutic effect of Agalsidase Beta. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Antipsychotic Agents (Phenothiazines): Antimalarial Agents may increase the serum concentration of Antipsychotic Agents (Phenothiazines). Risk C: Monitor therapy
Artemether and Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Artemether and Lumefantrine. Management: Artemether/lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. If combined, monitor patients for increased toxicities of both agents, including QTc interval prolongation. Risk D: Consider therapy modification
Cardiac Glycosides: Aminoquinolines (Antimalarial) may increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of Hydroxychloroquine. Risk X: Avoid combination
Ciprofloxacin (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Ciprofloxacin (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Ciprofloxacin (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Ciprofloxacin (Systemic). Risk C: Monitor therapy
Citalopram: May enhance the hypoglycemic effect of Hydroxychloroquine. Hydroxychloroquine may enhance the QTc-prolonging effect of Citalopram. Risk C: Monitor therapy
CycloSPORINE (Systemic): Hydroxychloroquine may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Dapsone (Systemic): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Dapsone (Systemic) may enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Risk D: Consider therapy modification
Dapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased. Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Risk D: Consider therapy modification
Escitalopram: May enhance the hypoglycemic effect of Hydroxychloroquine. Hydroxychloroquine may enhance the QTc-prolonging effect of Escitalopram. Risk C: Monitor therapy
Gemifloxacin: Hydroxychloroquine may enhance the hyperglycemic effect of Gemifloxacin. Hydroxychloroquine may enhance the hypoglycemic effect of Gemifloxacin. Hydroxychloroquine may enhance the QTc-prolonging effect of Gemifloxacin. Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Levofloxacin-Containing Products (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic). Risk C: Monitor therapy
Levoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Levoketoconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Mefloquine: Aminoquinolines (Antimalarial) may enhance the adverse/toxic effect of Mefloquine. Specifically, the risk for QTc-prolongation and the risk for convulsions may be increased. Mefloquine may increase the serum concentration of Aminoquinolines (Antimalarial). Management: Avoid concurrent use, and delay administration of mefloquine until at least 12 hours after the last dose of an aminoquinoline antimalarial when possible. Risk X: Avoid combination
Metoprolol: Hydroxychloroquine may increase the serum concentration of Metoprolol. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Moxifloxacin (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Moxifloxacin (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Moxifloxacin (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Rabies Vaccine: Aminoquinolines (Antimalarial) may diminish the therapeutic effect of Rabies Vaccine. Management: If administration of rabies post-exposure vaccine series is required while receiving aminoquinoline therapy, it is recommended to administer a 5th dose of the rabies vaccine. Risk D: Consider therapy modification
Remdesivir: Hydroxychloroquine may diminish the therapeutic effect of Remdesivir. Risk X: Avoid combination
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Sparfloxacin: Hydroxychloroquine may enhance the hyperglycemic effect of Sparfloxacin. Hydroxychloroquine may enhance the hypoglycemic effect of Sparfloxacin. Hydroxychloroquine may enhance the QTc-prolonging effect of Sparfloxacin. Risk C: Monitor therapy
Tamoxifen: May enhance the adverse/toxic effect of Hydroxychloroquine. Specifically, concomitant use of tamoxifen and hydroxychloroquine may increase the risk of retinal toxicity. Risk C: Monitor therapy
Hydroxychloroquine is recommended for use in patients with rheumatic and musculoskeletal diseases who are planning to become pregnant. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]).
Information related to paternal use of hydroxychloroquine is limited; however, available data have not shown hydroxychloroquine adversely impacts male fertility or increases the risk of adverse pregnancy outcomes when used prior to conception (Bermas 2019; Mouyis 2019). Hydroxychloroquine is recommended for use in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).
Hydroxychloroquine can be detected in the cord blood at delivery in concentrations similar to those in the maternal serum (Costedoat-Chalumeau 2002).
Adverse perinatal outcomes have not been associated with daily maternal doses of hydroxychloroquine ≤400 mg (Bérard 2021; Birru Talabi 2020; Costedoat-Chalumeau 2003; Diav-Citrin 2013; Huybrechts 2020). Retinal toxicity is a known risk following long-term use or high doses of hydroxychloroquine. Although animal reproduction studies have shown accumulation of chloroquine in fetal ocular tissues, an association between hydroxychloroquine and fetal ocular toxicity has not been confirmed in available human studies (Gaffar 2019; Levy 2001; Motta 2005; Osadchy 2011).
Maternal lupus is associated with adverse maternal and fetal events. If pregnancy is detected during therapy, hydroxychloroquine should not be stopped; cessation of hydroxychloroquine could precipitate a flare in maternal disease. Continued treatment is needed to control maternal disease and decrease the risk of maternal thrombosis and congenital heart block (Baer 2011; Izmirly 2012; Levy 2001; Petri 2020a; Tunks 2013).
Available guidelines recommend treatment with hydroxychloroquine for systemic lupus erythematosus (SLE) during pregnancy. Hydroxychloroquine may be beneficial for some pregnant patients with antiphospholipid syndrome (ACR [Sammaritano 2020]; EULAR [Andreoli 2017]).
Malaria infection in pregnant patients may be more severe than in nonpregnant patients and has a high risk of maternal and perinatal morbidity and mortality. Therefore, pregnant patients and patients who are likely to become pregnant are advised to avoid travel to malaria-risk areas. When travel is unavoidable, pregnant patients should take precautions to avoid mosquito bites and use effective prophylactic medications. Hydroxychloroquine is recommended for the treatment of uncomplicated malaria during pregnancy in chloroquine-sensitive regions (refer to current guidelines) (CDC 2020).
Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of hydroxychloroquine may be altered during pregnancy; however, dosage adjustments are not needed (Balevic 2019b). In one study, hydroxychloroquine concentrations ≤100 ng/mL correlated with increased disease activity and adverse maternal/fetal outcomes in patients with SLE, but there was no association between disease activity, pregnancy outcomes, and hydroxychloroquine blood levels in pregnant patients under treatment for LN (Balevic 2019a). Due to tissue binding, if hydroxychloroquine is discontinued, it would take 6 to 8 weeks to be completely eliminated.
Hydroxychloroquine and the desethylchloroquine metabolite are present in breast milk (Cissoko 2010; Costedoat-Chalumeau 2002; Nation 1984; Ostensen 1985; Peng 2019).
Breast milk concentrations of hydroxychloroquine were evaluated in 33 women. All women were treated with hydroxychloroquine for at least 1 year for various connective tissue diseases and were 1 to 16 weeks' postpartum. Maternal doses ranged from 200 mg every other day to 200 mg twice daily. Sampling occurred over a 12-hour dosing period. The average relative infant dose (RID) of hydroxychloroquine was calculated by the authors of the study to be 1.9% to 3.2% of the weight-adjusted maternal dose. The highest RID (9.8%) was observed in one woman taking hydroxychloroquine 200 mg twice daily (Peng 2019).
In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).
Infants exposed to hydroxychloroquine via breast milk following chronic maternal administration, including one infant who was exposed for 30 months (Cimaz 2004), have been monitored for adverse effects; no negative impact on vision, growth, development, or otherwise has been noted (Cimaz 2004; Motta 2002; Motta 2005; Peng 2019; Tincani 2001).
The manufacturer recommends that caution be exercised when administering hydroxychloroquine to breastfeeding patients; however, hydroxychloroquine is considered to be compatible for use in breastfeeding mothers with rheumatic and musculoskeletal diseases (ACR [Sammaritano 2020]). Clinicians should note that when hydroxychloroquine is administered to breastfeeding patients for malaria, insufficient amounts are transferred via breast milk to provide chemoprophylaxis to the infant (CDC Yellow Book 2020).
Note: Determinants for laboratory testing (ie, specific tests to monitor and frequency) should take into consideration patient's clinical status and duration of therapy (short-term versus long-term).
CBC (with differential), liver function, and renal function at baseline and periodically during therapy; blood glucose (if symptoms of hypoglycemia occur); muscle strength (especially proximal, as a symptom of neuromyopathy) during long-term therapy; in patients at elevated risk of QTc prolongation, monitor ECG at baseline and as clinically indicated to mitigate the risk of developing torsades de pointes; certain findings may require not initiating or discontinuing therapy. Serum concentration monitoring is recommended in the treatment of Q fever (CDC [Anderson 2013]).
Ophthalmologic exam at baseline (fundus examination within the first year plus visual fields and spectral-domain optical coherence tomography if maculopathy is present) to screen for retinal toxicity, followed by annual screening beginning after 5 years of use (or sooner if major risk factors are present) (Marmor [AAO 2016]). If ocular toxicity is suspected, monitor closely (retinal changes and visual disturbances may progress after drug discontinuation). Additionally, the manufacturer recommends an ocular exam include best corrected distance visual acuity and an automated threshold visual field of the central 10 degrees (24 degrees in patients of Asian ancestry as retinal toxicity may appear outside of the macula). Consider annual exams (without deferring 5 years) in patients with significant risk factors (eg, renal disease).
Data suggest that individual blood concentrations do not correlate closely with dosage, weight, or clinical effectiveness. However, blood levels may be useful in patients with renal disease or as an aid in assessing compliance (Melles 2014). One study suggested a correlation of blood concentrations with ocular toxicity (ie, highest tertile of 1,177 to 3,503 ng/mL) and suggested dosage reduction in these patients (Petri 2020b); however, routine testing is not recommended by some experts (Wallace 2020). For the treatment of Q fever, a target range of 0.8 to 1.2 mg/L is recommended (CDC [Anderson 2013]; Petri 2020b).
Antimalarial: Interferes with digestive vacuole function within sensitive malarial parasites by increasing the pH and interfering with lysosomal degradation of hemoglobin; inhibits locomotion of neutrophils and chemotaxis of eosinophils; impairs complement-dependent antigen-antibody reactions.
Onset of action: Rheumatic disease: May require several weeks to respond
Absorption: Incomplete and variable (~70% [range: 25 to 100%]) (Tett 1993)
Protein binding: ~40%, primarily albumin (Tett 1993)
Metabolism: Hepatic; metabolites include bidesethylchloroquine, desethylhydroxychloroquine, and desethylchloroquine (McChesney 1966)
Half-life elimination: ~40 days (Tett 1993)
Excretion: Urine (15% to 25% [Tett 1993]; as metabolites and unchanged drug [up to 60%, McChesney 1966]); may be enhanced by urinary acidification
Tablets (Hydroxychloroquine Sulfate Oral)
100 mg (per each): $2.24
200 mg (per each): $0.40 - $4.36
300 mg (per each): $6.72
400 mg (per each): $8.96
Tablets (Plaquenil Oral)
200 mg (per each): $0.18
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